Carbohydrate medical solution and sulphite stabilisator in a multiple compartment container and use thereof

ABSTRACT

The invention relates to a multiple compartment container for sterile medical solutions, particularly solutions for peritoneal dialysis containing a carbohydrate stabilisation compound, a carbohydrate medical solution containing said carbohydrate stabilisation compound and a method for the preparation thereof.

TECHNICAL FIELD

[0001] The present invention relates to multiple compartment containersincluding sterile medical solutions, in which at least one solutioncontains carbohydrate compounds. The invention further relates tostabilising carbohydrates in a sterile medical solution.

BACKGROUND

[0002] Sterilisation of medical solutions such as, for example,peritoneal dialyses (PD) solutions, is commonly performed through theaddition of energy, either in the form of radiation or heat.WO-A-9705852 discloses a multiple compartment container includingsterile peritoneal dialyses solutions, which is heat-sterilised in anautoclave.

[0003] In recent years scientists have become aware of the toxicity ofdecomposition compounds of carbohydrates in PD solutions. Wieslander etal., reported that all major brands of commercial PD solutions weretoxic in contrast to PD solutions sterilised by filtration (Wieslanderet al., 1991, Kidney Int, 40:77-79). The PD solutions were tested afterdilution with cell growth media on cultured fibroblasts. Furthermore,Wieslander et al. have reported that the glucose degradation productsalso affect the functional responses involved in host defence(Wieslander et al., 1995, Peritoneal Dialysis Int, 15 (suppl).

[0004] A patient on peritoneal dialysis (PD) uses between 8 and 20litres of dialysis solution every day, depending on the treatment. Thisresults in the consumption of 3-7 tons of solution with 1.5-4% glucose(50-175 kg pure glucose) every year. (Wieslander, 1996, Nephrol DialTransplant 11:958-959), which if the glucose undergoes decompositionalso means a non-negligible amount of decomposition compounds.Furthermore, it is well known that some patients experience pain duringinflow of the dialysis fluid. It has been speculated that the pain couldbe the result of glucose degradation (Henderson et al., 1985 Frontiersin peritoneal dialysis, ed. Winchester, N.Y.: Field, Rich, 261-264) andthat these degradation products mediate basal cytotoxicity (Barile F A,1994, Introduction to in vitro cytotoxicity. Florida: CRC Press, 27-35).This means that they act upon fundamental life processes, which involvestructures and functions common to all living cells such as membraneintegrity, mitochondrial activity, or synthesis of proteins and DNA.These basal cell functions support organ specific cell functions. Thus,glucose degradation products capable of affecting basal cell activitiesare likely to interfere with specialised cell functions such as IL-1βrelease from mononuclear cells.

[0005] Glucose, an osmotic agent commonly used in PD solutions is knownto degrade into carbonyls such as formaldehyde, acetaldehyde,metylglyoxal, 3-deoxyglucosone and glyoxal.

[0006] Sulphite compounds have commonly been used as antioxidant inparenteral emergency drugs to prevent oxidation. The mechanism ofdecomposition of carbohydrates in PD solutions has appears however tohave less to do with oxidation and sulphite is not intended to be usedas an antioxidant in vitro in the present invention. Further, theanti-microbial or antioxidant compounds in parenteral emergency drugsare typically used in concentration which deliver 0.5 to 2 mg ofsulphite per ml of undiluted drug injection (Smolinske S, 1992, Clinicaltoxicology 30:597-606). Such concentrations for preventing oxidationcould not be used in PD solutions since they would administer too muchsulphite to the patient resulting in adverse toxic effects.

SUMMARY OF THE INVENTION

[0007] On the above background it is an object of the present inventionto provide a multiple compartment container for sterile medicalsolutions of the kind referred to above in which decomposition ofcarbohydrates and/or the negative effects of the decomposition productsare reduced. The multiple compartment container comprises at least onesulphite compound in one or more of the compartments to stabilisedecomposition of carbohydrates or to scavenge decomposition productsformed during sterilisation and/or storage.

[0008] The invention further relates to a medical solution wherein thesolution contains at least one carbohydrate compound and at least onesulphite compound to stabilise decomposition of the carbohydrates or toscavenge decomposition products formed from the carbohydrates duringsterilisation or storage of the medical solutions.

[0009] Additionally the invention relates to a method of stabilising acarbohydrate containing solution wherein the solution contains at leastone sulphite compound to stabilise decomposition of carbohydrates or toscavenge decomposition products formed during sterilisation and/orstorage.

[0010] Furthermore the invention relates to the use of a carbohydratecontaining solution for the preparation of a multiple compartmentcontainer.

[0011] Finally, the invention relates to use of a carbohydratecontaining solution for the preparation of a multiple compartmentcontainer for the treatment of a patient in need thereof.

BRIEF DESCRIPTION OF THE DRAWING

[0012] In the following detailed portion of the present description, theinvention will be explained in more detail with reference to anexemplary embodiment shown in the drawings, in which FIG. 1 is a frontalview on a multiple compartment container according to an embodiment ofthe invention.

DETAILED DESCRIPTION OF THE INVENTION

[0013] The invention is intended for use in treatments of diseases suchas uremic disorder or kidney malfunctions, including for exampletreatments of diseases using peritoneal dialysis.

[0014] Definitions

[0015] The term “multiple compartment container for a medical solution”is intended to mean any container comprising more than one compartment,particularly two or three but not limited to three, compartments. Oneexample is a multiple compartment container used for peritoneal dialysiscontaining medical solutions, which are sold under the brand Physioneal®and Gambrosol® trio.

[0016] The term “medical solution” is intended to mean any solutionuseful for medicinal purposes in which, a carbohydrate may be presentand in which the carbohydrate undergoes decomposition during either thesterilisation procedure or storage resulting in disadvantageousdecomposition products unfavourable for living cells. Decompositionproducts contemplated are for example products such as mono anddicarbonyl compounds, formaldehyde, acetaldehyde, methylglyoxal,3-deoxyglucosone and glyoxal or the like. The storage conditions couldbe any conventional storage condition, such as room temperature for 2years. One example of a medical solution is a solution, present in oneor more of the compartments, used for peritoneal dialysis.

[0017] The term “final solution” is intended to mean a solution obtainedby mixing one or more of the medical solutions in the container.

[0018] The term “peritoneal dialysis solution” is intended to mean asolution comprising an electrolyte, a buffer and an osmotically activecompound, wherein the electrolyte comprises ions, such as sodium,potassium, calcium and magnesium; the buffer comprises components, suchas acetate, lactate and bicarbonate; and the osmotic compound is acarbohydrate as defmed hereinafter. Examples of medical solutions foruse as peritoneal dialysis solutions may be found in Wieslander et al.,1991, Kidney Int 40:77-79. The peritoneal dialysis solution could, priorto dialysis, be present in one or more compartments. In the case ofmultiple compartments the solutions are mixed prior to peritonealdialysis.

[0019] The term “carbohydrate compound” is intended to mean sugars orsugars acids such as glucose, fructose, mannose, aldonic, alduronic,aldaric acids and their esters with saccharides or a polymer of glucose,fructose, mannose, aldonic, alduronic, aldaric acids and their esterswith saccharides or a synthetic form of glucose, fructose, mannose,aldonic, alduronic, aldaric acids and their esters with saccharides orderivatives and mixtures thereof.

[0020] The term “sulphite compound” is intended to mean a sulphitecontaining compound with the properties to reduce the content ofdecomposition products, by for example stabilising the solution,including preventing the generation of decomposition products, orscavenging already formed decomposition products, produced duringsterilisation and/or storage of medical solutions containingcarbohydrate compounds, as defined above.

[0021] Furthermore, the sulphite compound could be used as anantioxidant or to scavenge toxic or allergenic compounds in vivo, suchas in the body fluids. Examples of such toxic or allergenic compoundsare metylglyoxal, 3-deoxyglucosone and glyoxal. The effect of thesulphite compound can be measured according to the method “Analysis ofglucose degradation products” mentioned under “Material and Methods”hereinafter. Examples of such sulphite compounds are any sulphite,having a positive counter ion, such as sodium, potassium, calcium,magnesium and ammonium, for example HSO₃ ⁻, S₂O₅ ²⁻ and SO₃ ²⁻. Examplesof sulphite compounds to be used are NaHSO₃, Na₂S₂O₅ and Na₂SO₃ or anyother of sulphite compound or derivative thereof, natural or synthetic,or mixtures thereof.

[0022] The term “stabilising” is intended to mean preventing thegeneration of decomposition products, or scavenging already formeddecomposition products, produced during sterilisation and/or storage ofmedical solutions containing carbohydrate compounds

[0023] The term “carbohydrate decomposition products” is intended tomean products produced in a carbohydrate solution during any kind ofsterilisation and/or during storage, which are products obtained fromdecomposition of carbohydrates, such as glucose and toxic to eucaryoticand procaryotic cells. Specifically contemplated are mono and dicarbonylcompounds, such as formaldehyde, acetaldehyde, methylglyoxal,3-deoxyglucosone and glyoxal or the like. The toxicity can be measuredaccording to the method “in vitro assay for cytotoxity” mentioned in“Materials and Methods hereinafter.

[0024] The term “sterilisation” is intended to mean any kind ofsterilisation, such as radiation, pressure, heat, UV-radiation,radioactive radiation, sterile filtration, radiation using micro wavesor other sterilisation methods. Furthermore the sterilisation can beperformed using different approaches such as short sterilisation time ata high temperature, sterilisation at low pH, sterilisation with highglucose concentration after removal of catalytic substances.

[0025] Multiple Compartment Containers Employing a Medical Solution.

[0026] The invention relates to multiple compartment containers forsterile medical solutions, particularly solutions for peritonealdialysis (PD), wherein the medical solutions are present in one or morecompartments. One or more of the compartments comprises a carbohydrateand at least one sulphite compound in order to reduce the amount of thecarbohydrate decomposition products produced during sterilisation and/orstorage. Furthermore one or more of the compartments may include anelectrolyte, a buffer and any other pharmaceutically acceptable additiveor other component.

[0027] Additionally, the container comprises at least two compartments,preferably three or more compartments, most preferably three. In atleast one of the compartments there is provided a carbohydrate compoundin solution and in at least one of the compartments there is provided asulphite compound to reduce the formation or scavenge already produceddecomposition products formed from carbohydrate.

[0028] Furthermore the “sulphite compound” could be used as anantioxidant or to scavenge toxic or allergenic compounds in vivo, suchas in the body fluids. Commonly used medical solutions either in singleor multiple compartment container(s) for peritoneal dialysis preferablycontain glucose in the final solution in a concentration in the range of1.5 to 4,0% preferably substantially 1.5, 2.5 or 4% by weight (based onthe final solution).

[0029]FIG. 1 shows a preferred embodiment of the container, in this casea three-compartment bag. The bag 1 is made from a continuous tube of aplastics material, which is sealed at both ends by sealing borders 2,3.

[0030] As shown in FIG. 1 each sealing border comprises severalembossments 4 and apertures 5,6,7. The embossments 4 enhance thestability of the border 2. The aperture 5 in the upper border 2 isintended for hanging the bag during use and the apertures 6,7 in thelower border 3 are for fixation of the bag during the manufacturingoperation.

[0031] The lower border 3 is also provided with an outlet tube 14, whichconnects compartment 9 with the consumer, for example a catheter endingin the abdominal cavity of a patient for peritoneal dialysis. Often tube14 terminates in a luer connector (not shown in FIG. 1).

[0032] Furthermore, border 3 is provided with a filling tube 12, amedicament tube 15 including a removable cap 16. When cap 16 is removed,tube 15 forms an entrance site for introducing any type of beneficialagent or medicament into compartment 9 as desired, such as antibiotics.

[0033] The bag 1 is divided into three compartments 9,44,45 by weldingseal lines 41,42,43. The upper compartments 44,45 divided by weldingseal line 11 are of equal size and separated form the lower compartment8 by two sloping welding lines 42,43. Thus there is formed a first uppercompartment 44 and a second upper compartment 45, each being accessedvia introduction tubes 46,47. The large lower compartment 9 comprisesthe electrolytes necessary for the solution to be formed (finalsolution), such as NaCl, MgCl₂, lactate etc., dissolved in water in amanner known per se.

[0034] The first compartment 44 comprises glucose solution having aconcentration of about 30% and the second compartment 45 comprises aglucose solution having a concentration of about 50%.

[0035] When breaking the breakable portion of connection tube 48, thecontents of the first compartment 44 is mixed with the contents of thelower compartment 9 to form a peritoneal dialysis solution having aconcentration of 1.5% of glucose. If the breakable portion of connectiontube 49 is broken, the contents of compartment 45 is mixed with thecontents of both compartment 9 thereby forming a dialysis solutionhaving a concentration of about 2.5% of glucose. If both breakableportions of connection tubes 48,49 are broken, the contents of bothcompartments 44 and 45 are mixed with the contents of compartment 9thereby to form a dialysis solution having a concentration of about 4%of glucose. The above dialysis solutions formed by mixing at least oneof the glucose containing compartments.

[0036] If the bag should be used as a nutritional solution, the largecompartment 9 may comprise only NaCl or any other suitable compositionas used today but excluding glucose.

[0037] It is mentioned that the glucose can be exchanged with a glucoselike component, such as glucose polymers, as an osmotic agent.

[0038] Furthermore, the sterile medical solutions comprising acarbohydrate, may include an electrolyte, a buffer such as lactate andany other pharmaceutically acceptable additive.

[0039] According to one embodiment of the invention the carbohydratecompound is separately provided in one or more compartments, the rest ofthe peritoneal dialysis solution compounds being provided in one or morethe other compartments. The sulphite compound(s) may be present in oneor more of said compartments or separately presented in one or morecompartments. The sulphite compound(s) may be introduced in any of thecarbohydrate or electrolyte solution compartments before or aftersterilisation. However, some or all components of the medicalsolution(s) and the sulphite compound are mixed prior to peritonealdialysis to obtain a final solution.

[0040] If a monosulphite compound such a bisulphate is used, it ispreferably added to the carbohydrate and/or the electrolyte compartmentin an amount to give a final solution within the range of 0.01-10 mM,preferably 0.05-1 mM, most preferably 0.05-0.5 mM. If a disulphitecompound is used it is preferably added to the carbohydrate compartmentin an amount to give a final solution within the range of 0.005-5 mM,preferably 0.025-0.5 mM, most preferably about 0.025-0.25 mM.

[0041] If a disulphite compound is used it is preferably added in anamount to give a final solution which is half of the concentration usedfor the corresponding monosulphite compound.

[0042] The pH of the solution in the carbohydrate compartment ispreferably between pH 2.0-7.5, more preferably pH 2-5.5, even morepreferably pH 3-4 and most preferably about pH 3.2. The pH of the finalsolution is preferably between 5.0-8.0, more preferably between 6.5-8.0,most preferably between 7.0-7.5 or absolutely most preferably 7.4.

[0043] Additionally, in a preferred embodiment, the multiple compartmentcontainer containing the medical solution is sterilised. Anyconventional methods and apparatus for sterilisation may be used, suchas those mentioned under the definition of the term “sterilisation”.Preferably the sterilisation is performed by heat treatment mostpreferable at about 121° C. for 20 minutes (Ph. Eur. (current)).

[0044] Solution

[0045] The invention further relates to a medical solution comprising atleast one sulphite compound to be included for the ability to reduce theconcentration of decomposition products formed from a carbohydrate bystabilisation or scavenging already formed decomposition products,obtained during sterilisation and/or storage of solutions containingcarbohydrate compounds, as defined above. Furthermore the “sulphitecompound” could be used as an antioxidant or to scavenge toxic orallergenic compounds in vivo, such as in the body fluids.

[0046] The invention further relates to a medical solution such as asolution used for peritoneal dialysis either in a single or a multiplecompartment container, comprising at least one sulphite compound to beincluded for the ability to reduce decomposition of a carbohydratepresent in the solution exposed to sterilisation.

[0047] If a monosulphite compound such a bisulphite is used, it ispreferably added to the carbohydrate and/or the electrolyte compartmentin an amount to give a final solution with a concentration within therange of 0.01-10 mM, preferably 0.05-1 mM, most preferably about0.05-0.5 mM. If a disulphite compound is used it is preferably added tothe carbohydrate compartment in an amount to give a final solution witha concentration within the range of 0.005-5 mM, preferably 0.025-0.5 mM,most preferably 0.025-0.25 mM.

[0048] If a disulphite compound is used it is preferably added in anamount to give a final solution which is half of the concentration usedfor the corresponding monosulphite compound.

[0049] The pH of the carbohydrate solution is not critical and could bein any range, suitable the pH is between pH 2.0-7.5, more preferably pH2-5.5, even more preferably pH 3-4 and even more preferably about pH3.2. The pH of the final solution is preferably between 5.0-8.0 and morepreferably 6.5-8.0 and most preferably 7.0-7.5.

[0050] Preferably the medical solution is a sterile medical solution.

[0051] Additionally, the sulphite compound may be provided to thecarbohydrate solution prior or after sterilisation.

[0052] Furthermore, the sterilisation is performed using anyconventional sterilisation method as defined above under the term“sterilisation”. Preferably the sterilisation is performed by heattreatment within the range of 100-150° C., for 1-130 minutes, morepreferably at 121° C. for 20 minutes (Ph. Eur. (current)).

[0053] The solution may be any medical solution which comprises acarbohydrate with or without other components. Preferably the solutionis a medical solution such as a solution used for peritoneal dialysis,preferably medical solution(s) for single or multiple compartmentcontainer(s) for peritoneal dialysis, more preferably two or threecompartment containers, even more preferably a three compartmentcontainer. Medical solutions used for peritoneal dialysis preferablycontain glucose in an amount to give a glucose concentration in therange of 1.5 to 4%, preferably about 1.5, 2.5 or 4% by weight in thefinal solution (based on the total final solution).

[0054] Additionally the medical solution is a solution used to scavengetoxic or allergenic compounds in vivo, preferably a medical solutionused to scavenge toxic or allergenic compounds in body fluids.

[0055] Method

[0056] The invention further relates to a method for stabilising orscavenging the decomposition of carbohydrate components produced in amedical solution during sterilisation and/or storage, comprisingproviding a sulphite compound to the solution prior or after thesterilisation process in order to reduce decomposition of thecarbohydrate components in the medical solution.

[0057] Preferably the method is used for preparation of medicalsolution(s) used for peritoneal dialysis.

[0058] Even more preferably the medical solution (s) is/are used in amultiple compartment container for peritoneal dialysis, such as a threecompartment container.

[0059] Preferably, the method is used for preparation of a multiplecompartment container used for peritoneal dialysis, wherein the sulphitecompound may be added either to the carbohydrate compartment or to theelectrolyte compartment of a multiple compartment.

[0060] If a monosulphite compound is used it is preferably added to thecarbohydrate solution in an amount to give a concentration in the finalsolution within the range of 0.01-10 mM, preferably 0.05-1 mM, mostpreferably 0.05-0.5 mM.

[0061] If a disulphite compound is used it is preferably added to thecarbohydrate solution in an amount to give a concentration in the finalsolution within the range of 0.005-5 mM, preferably 0.025-0.5 mM, mostpreferably 0.025-0.25 mM.

[0062] When a disulphite compound is used it is also preferably added inan amount to give a concentration in the final solution which is half ofthe concentration used for a corresponding monosulphite compound.

[0063] The pH of the carbohydrate compartment is preferably between pH2.0-7.5, more preferably pH 2-5.5, even more preferably pH 3-4 and mostpreferably about pH 3.2.

[0064] More preferably the method is used for the preparation of asterile multiple compartment.

[0065] Additionally, the sulphite compound is provided to thecarbohydrate solution prior or after sterilisation.

[0066] Furthermore, the sterilisation is performed using anyconventional sterilisation method as defined above under the term“sterilisation”. Preferably the sterilisation is performed by heattreatment within the range of 100-150° C., for 1-130 minutes, morepreferably at 121° C. for 20 minutes (Ph. Eur. (current)).

[0067] The method according to the invention is intended to be used formedical solutions, in which the medical solution needs to be sterile, bya method as defmed under the term “sterilisation”, and preferably themethod will be used for the preparation of medical solutions used forperitoneal dialysis or the like. By way of adding a sulphite compound insmall amounts to the solution either prior or after sterilisation,decomposition of the carbohydrate components into toxic compounds in thesolution is prevented or the toxic compounds are scavenged. Preferably,medical solutions to be used for peritoneal dialysis, preferably containglucose in an amount to give a glucose concentration range between 1.5to 4%, preferably about 1.5, 2.5 or 4% by weight in the final solution.

[0068] Furthermore the sulphite compound could be used as an antioxidantor to scavenge toxic or allergenic compounds in vivo, such as in thebody fluids.

[0069] Additionally the invention provides the use of a carbohydratecontaining solution for the preparation of a multiple compartmentcontainer, preferably a three compartment container, suitable forperitoneal dialysis.

[0070] Specifically the invention provides the use of a carbohydratecontaining solution for the preparation of a multiple compartmentcontainer for the treatment of an animal in need thereof.

MATERIALS AND METHODS

[0071] Determination of Glucose Degradation Products:

[0072] Chemicals: Acetonitrile (Lab Scan, Ireland) and methanol (LabScan, Ireland) were of HPLC grade. 2,3- diaminonaphtalene was suppliedby ICN, USA. 3-deoxyglucosone 56% (weight/weight) was synthesised by T.Henle Technische Univerität Dresden. Sodiumphosphate p.a. and Glyoxal30% (weight/volume) supplied by Merck (Germany), methylglyoxal 40%(weight/volume), 2,4-di-nitrophenylhydrazine (2,4-DNPH) and1,2-phenylenediamine were supplied by Sigma Chemical (USA). Acetaldehydep.a. was supplied by Fluka (Germany).

[0073] Equipment: Two HPLC systems were used for the determination ofglucose degradation products (GDP). One HPLC consisted of an HewlettPackard liquid chromatograph serie 1050 equipped with an UV-detector andan autosampler. The second HPLC system consisted of an Hewlett Packardliquid chromatograph serie 1100 equipped with an autosampler and WatersRefractive Index detector model 410. Hewlett Packard Chem Stationsoftware rev. A.06.03, NT 4.0 was used for the data handling.

[0074] Determination of 3-deoxyglucosone (3-DG): 3-DG was determinedusing 2,3-diaminonaphtalene as derivative reagent. The samples werediluted 50 times to a total volume of 1 ml prior to analysis. Thestandards were prepared in the range 1-6 μM. Standards and samples wereprepared by adding 100μl 0.1% (2,3-diaminonaphtalene to 1 ml sample andincubated for 16 hours in room temperature in dark. The analyticalcolumn was a Water Symmetry C18 column (5μm, 25 cm ×4, 6 mm). Theelution of the substance was performed at constant flow rate of 1.0ml/min by using a gradient of acetonitrile/water. The percentage ofacetonitrile/water (volume/volume) was initially 25/75, and 12 minuteslater 25/75, at 15 minutes 60/40 and at the gradient stop 30 minutes60/40. The wavelength was set at 268 nm and the injected volume was 20μl. The limit of quantification was 1 μM.

[0075] Determination of acetaldehyde and formaldehyde: The samples forthe determination of acetaldehyde were diluted 20 times to a finalvolume of 4 ml, prior to analysis. Acetaldehyde was prepared ashydrazone derivatives using 2,4-DNPH as derivative reagent. Thestandards were prepared in range 1.1-11.4 μM acetaldehyde, and 1.7-16.7μM formaldehyde. Standards and samples were prepared by adding 2 ml0.08% (weight/volume) 2,4-DNPH to 4 ml of each sample. The sample wereconcentrated on a solid phase extraction C18 column (Bond Elut LRC 200mg/3 ml) and after rinsing with water, eluted with 1.6 ml acetonitrile.The analytical column was a Supelco C18 column (5 μm, 15 cm×4,6 mm). Theelution of the substances was performed at constant flow of 1.7 ml/minby using a linear gradient of acetonitrile/water. The percentageacetonitrile/water (volume/volume) was initially 35/65 and at thegradient stop 12 minutes later 80/20. The wavelenght was set at 240 nmand the injected volume was 20 μl. The limit of quantification was foracetaldehyde. 1.1 μM. And for formaldehyde 1.7 μM.

[0076] Determination of glyoxal and methylglyoxal: Glyoxal andmethylglyoxal were determined as quinoxalines using1,2-phenylenediamine. The standards were prepared in the range 3.5-51.7μM methylglyoxal. Standards and samples were prepared by adding 0.6 ml0.4% (volume/volume) 1,2-phenylenediamine to 1 ml of each sample. Theanalytical column was Supelco C18 column (5 μm, 25 cm×4,6 mm). Theelution of the substances was performed at constant flow of 1.0 ml/minusing a mobile phase of initial 25% (volume/volume) acetonitrile and 75%(weight/volume) 0.05 M sodiumphosphate. At the gradient at 6 minutes themobile phase was 30% acetonitrile and 70% millipore water and atgradient stop 9 minutes the percentages were 25/75. The wavelength wasset at 312 nm and the injected volume was 20 μl. The limit ofquantification for glyoxal was 3.5 μM and for methylglyoxal 2.8 μM.

[0077] In Vitro Assay for Cytotoxicity

[0078] Medical solutions used for peritoneal dialysis were mixed withone part cell growth medium and 10% (volume/volume) fetal calf serum wasadded (Wieslander et al., 1991, Kidney Int. 40:77-79). Basalcytotoxicity of medical solution used for peritoneal dialysis weredetermined on mouse fibroblasts cells L-929 (CCL-1; ATTC, Rockville,Md., USA) as described earlier (Wieslander et al. 1993, Advances inPeritoneal Dialys, 9:31-35) and expressed as inhibition of cellgrowth(ICG).

EXAMPLE 1

[0079] Three Compartment Container with Sulphite in the GlucoseCompartment

[0080] A multiple compartment container as shown in FIG. 1, containingfollowing medical solutions in the three compartments 44, 45 and 9.

[0081] Compartment 44 containing 100 ml of the composition: glucose 30%calcium 20 mM magnesium 5 mM sodium 132 mM bisulphite 1 mM pH 3.2

[0082] Compartment 45 contains 100 ml of the composition: glucose 50%calcium 33 mM magnesium 8 mM sodium 132 mM bisulphite 1 mM pH 3.2

[0083] Compartment 9 contains 1900 ml with the composition: bicarbonate40 mM sodium 132 mM pH 6.7

[0084] By mixing the contents of compartment 44 and compartment 9, afinal solution suited for peritoneal dialysis is obtained with thefollowing concentrations: glucose 1.5% calcium 1.0 mM bicarbonate 38 mMsodium 132 mM magnesium 0.25 mM bisulphite 0.05 mM

[0085] By mixing the contents of compartment 45 and compartment 9, afinal solution suited for peritoneal dialysis is obtained with thefollowing concentrations: glucose 2.5% calcium 1.65 mM bicarbonate 38 mMsodium 132 mM magnesium 0.4 mM bisulphite 0.05 mM

[0086] By mixing the contents of both compartments 44 and 45 with thecontents of compartment 9, a final solution suited for peritonealdialysis is obtained with the following concentrations: glucose 4.0%calcium 2.5 mM bicarbonate 36 mM sodium 132 mM magnesium 0.6 mMbisulphite 0.1 mM

EXAMPLE 2

[0087] Three Compartment Container with Sulphite in ElectrolyteCompartment

[0088] A multiple compartment container as shown in FIG. 1, containingfollowing medical solutions in the three compartments 44,45 and 9.

[0089] Compartment 44 contains 100 ml of the composition: glucose 30%calcium 20 mM magnesium 5 mM sodium 132 mM pH 3.2

[0090] Compartment 45 contains 100 ml of the composition: glucose 50%calcium 33 mM magnesium 8 mM sodium 132 mM pH 3.2

[0091] Compartment 9 contains 1900 ml with the composition: bicarbonate40 mM sodium 132 mM bisulphite 0.1 mM pH 6.7

[0092] By mixing the contents of compartment 44 and compartment 9, afinal solution suited for peritoneal dialysis is obtained with thefollowing concentration: glucose 1.5% calcium 1.0 mM bicarbonate 38 mMsodium 132 mM magnesium 0.25 mM bisulphite 0.095 mM

[0093] By mixing the contents of compartment 45 and compartment 9, afinal solution suite for peritoneal dialysis is obtained with thefollowing concentration: glucose 2.5% calcium 1.65 mM bicarbonate 38 mMsodium 132 mM magnesium 0.4 mM bisulphite 0.095 mM

[0094] By mixing the contents of both compartments 44 and 45 with thecontents of compartment 9, a final solution suited for peritonealdialysis is obtained with the following concentration: glucose 4.0%calcium 2.5 mM bicarbonate 36 mM sodium 132 mM magnesium 0.6 mMbisulphite 0.090 mM

EXAMPLE 3

[0095] Two Compartment Container with Sulphite in Glucose Compartment orThree Compartment Container with both Glucose Compartments Mixed.

[0096] The solutions used in example 3 and 4 were as described inexample 1 and 2 except for that 50% glucose was used in all glucosecompartments giving slightly different volumes for the compartments.

[0097] Two different sets of solutions were prepared, one electrolytecompartment with the volume 1.875 L and one glucose containingcompartment with different amounts of bisulphite added, this volume was125 ml. The solutions were sterilised at 121° C. for 1 hour and mixedpost sterilisation. The concentrations post mixing of electrolytes were132 mM Na⁺, 1.35 mM Ca⁺, 0.25 mM Mg²⁺, 95.2 mM Cl⁻ and 40 mM lactate.

[0098] The concentration of glucose were 4% (w/v) and the concentrationof sulphite were 0.0.01, 0.05, 0.1, 0.2 and 0.5 mM in the finalsolution.

[0099] The sterilised solutions were analysed in the In vitro assay ofcytotoxicity mentioned under Materials & Methods. The results from theassay showed that an increase of the sodium bisulphite resulted in adecrease of the ICG value, which means that there is a decrease in thecontent of the toxic decomposition products after addition of a sodiumbisulphite.

EXAMPLE 4

[0100] Two Compartment Container with Sulphite in ElectrolyteCompartment or Three Compartment Container with both GlucoseCompartments Mixed

[0101] As described in example 3 except for that sulphite was added tothe electrolyte compartment. The concentrations of electrolytes, glucoseand sulphite in the final solution were as in example 3. The sterilisedsolutions were analysed as in example 3. The results from the assayshowed that an increase of the sodium bisulphite resulted in a decreaseof the ICG value, which means that there is a decrease in the content ofthe toxic decomposition products.

EXAMPLE 5

[0102] Analysis of a Solution with or without Sulphite for the Presenceof Formaldehyde Acetaldehyde and ICG.

[0103] Three solutions containing 132 mM Na⁺, 1.35 mM Ca²⁺, 0.25 mMMg²⁺, 95.2 mM Cl⁻, 40 mM lactate and 1.5% glucose was heat sterilised at121° C. for 1 hour. The sterilised solutions were mixed with sodiumbisulphite to three different concentrations of sodium bisulphite (0,0.5, 1 mM). Three solutions containing 132 mM Na⁺, 1.35 mM Ca²⁺, 0.25 mMMg⁺, 95.2 mM Cl⁻, 40 mM lactate and 1.5% glucose were mixed with sodiumbisulfite to different concentration of sodium bisulphite (0, 0.5, 1 mM)and was heat sterilised at 121° C. for 1 hour.

[0104] The sterilised six solutions were analysed in the In vitro assayof cytotoxicity and determination of acetaldehyde and formaldehydementioned under Materials & Methods. The results from the In vitro assayof cytotoxicity showed that an increase of the sodium bisulphiteresulted in a decrease of the ICG value, which means that there is adecrease in the content of the toxic decomposition products. The resultsfrom the assay “determination of acetaldehyde and formaldehyde” showeddecreased levels of both acetaldehyde and formaldehyde in the solutionscontaining sodium bisulphite, even down to levels under detection limit.

1. Multiple compartment container for sterile medical solutions, whereinsaid solutions are present in two or more compartments, and at least oneof said solutions comprises a carbohydrate compound, characterised inthat at least one sulphite compound is present in one or more of saidcompartments.
 2. Multiple compartment container according to claim 1,wherein said sulphite compound is selected from the group consisting ofHSO₃ ⁻, S₂O₅ ²⁻or SO₃ ²⁻, having a positive counter ion or mixturesthereof, preferably NaHSO₃, Na₂S₂O₅ or Na₂SO₃ or a mixture thereof. 3.Multiple compartment container according claim 1 or 2, wherein saidsulphite compound is a monosulphite compound, the total amount ofmonosulphite compound in said container being equal to 0.01-10 mmol, perliter of the total amount of solution in said container, preferably0.05-1 mmol, per liter of the total amount of solution in saidcontainer, most preferably 0.05-0.5 mmol, per liter of the total amountof solution in said container.
 4. Multiple compartment containeraccording to claim 1 or 2, wherein said sulphite compound is adisulphite compound, the total amount of disulphite compound in saidcontainer being equal to 0.005-5 mmol per liter of the total amount ofsolution in said container, preferably 0.025-0.5 mmol, per liter of thetotal amount of solution in said container, most preferably 0.025-0.25mmol, per liter of the total amount of solution in said container. 5.Multiple compartment container according to claim 3 or 4, wherein the pHof the mixed solution in said container is between 5.0-8.0, morepreferably between 6.0-8.0, most preferably between 7.0-7.5.
 6. Multiplecompartment container according to any of claims 1-5, wherein saidcarbohydrate is glucose and the total amount of glucose in saidcontainer is about 4% by weight of the total amount of solution in saidcontainer.
 7. Multiple compartment container according claims 1 to 6,wherein said carbohydrate compound is not present in all compartments,preferably in only one of two compartments in a two compartment bag orin only two of three compartments in a three compartment bag. 8.Multiple compartment container according claim 7, wherein the pH of saidcompartments containing said carbohydrate compound is between 2.0 and7,5, preferably between 2.0 and 5,5, more preferably between 3 and 4 andmost preferably about 3,2.
 9. Multiple compartment container accordingto claim 7 or 8, wherein said sulphite is a monosulphite compound andwherein said concentration monosulphite after mixing of said differentsolutions give rise to a final solution with a concentration ofmonosulphite compound of 0.01-10 mM, preferably 0.05-1 mM, mostpreferably 0.025-0.25 mM.
 10. Multiple compartment container accordingto claim 7 or 8, wherein said sulphite is a disulphite compound andwherein said concentration disulphite after mixing of said differentsolutions give rise to a final solution with a concentration ofdisulphite compound of 0.005-5 mM, preferably 0.025-0.5 mM, mostpreferably 0.025-0.25 mM.
 11. Multiple compartment container accordingto any of claims 7 to 10, wherein said carbohydrate compound is glucoseand said container is a three compartment bag and wherein theconcentration of glucose after mixing of said different solutions giverise to a final solution in the range of 1.5 to 4%, preferably about1.5, 2.5 or 4% by weight of glucose based of the total amount of finalsolution.
 12. Multiple compartment container according to any of claims1-11, wherein said container is sterilised using heat treatment. 13.Multiple compartment container according to any of claims 1-12, whereinsaid multiple compartment container contains medical solutions forpreparing a final solution for peritoneal dialyses by mixing two or moreof said medical solutions.
 14. A sterile medical solution comprising acarbohydrate compound, at least one sulphite compound selected from thegroup consisting of HSO₃ ⁻, S₂O₅ ²⁻ or SO₃ ²⁻, having a positive counterion or mixtures thereof, preferably NaHSO₃, Na₂S₂O₅ or Na₂SO₃ or amixture thereof, wherein said sulphite compound is a monosulphitecompound, present in a concentration of between 0.01-10 mM or adisulphite compound, present in a concentration of between 0.005-5 mM.15. A sterile medical solution according to claim 14, wherein saidsulphite compound is a monosulphite compound, present in a concentrationof preferably 0.05-1 mM, most preferably 0.05-0.5 mM.
 16. A sterilemedical solution according to claim 14 or 15, wherein said solution isheat sterilised.
 17. A sterile medical solution according to any ofclaims 14-16, wherein said solution is a solution for peritonealdialysis.
 18. A sterile medical solution according to any of claims14-17, wherein said solution is used in a three compartment container.19. A method of stabilising a carbohydrate containing sterile medicalsolution wherein in that at least one sulphite compound is added to saidsolution in a concentration of preferably 0.05-1 mM, most preferably0.05-0.5 mM if said sulphite component is a monosulphite compound, andin a concentration of 0.005-5 mM, preferably 0.025-0.5 mM, mostpreferably 0.025-0.25 mM if said sulphite component is a disulphitecompound.
 20. A method according to claim 19, wherein said sulphitecompound is selected from the group consisting of HSO₃ ⁻, S₂O₅ ²⁻ or SO₃²⁻, having a positive counter ion or mixtures thereof, preferablyNaHSO₃, Na₂S₂O₅ or Na₂SO₃ or a mixture thereof.
 21. A method accordingto claim 19 or 20, wherein said solution is heat sterilised.
 22. Use ofa carbohydrate containing sterile medical solution according to any ofclaims 14-18 for the preparation of a multiple compartment containeraccording to any of claims 1-13.